Methods of producing hybrid antibodies

A method of producing an antibody, the method comprising:

• (a) providing a genetically modified mouse comprising in its germline:
• (i) a hybrid heavy chain immunoglobulin locus comprising human unrearranged heavy chain variable region gene segments operably linked to a mouse heavy chain constant region gene at an endogenous mouse heavy chain immunoglobulin locus, wherein rearrangement of the human heavy chain variable region gene segments in the mouse results in a rearranged human heavy chain variable region gene linked to the mouse heavy chain constant region gene;
• and
• (ii) a hybrid light chain immunoglobulin locus comprising human unrearranged light chain variable region gene segments operably linked to a mouse light chain constant region gene at an endogenous mouse light chain immunoglobulin locus, wherein rearrangement of the human light chain variable region gene segments in the mouse results in a rearranged human light chain variable region gene linked to the mouse light chain constant region gene, wherein the mouse in response to an antigen produces a hybrid antibody, the hybrid antibody comprising a heavy chain comprising a human heavy chain variable region encoded by the rearranged human heavy chain variable region gene and a mouse heavy chain constant region encoded by the mouse heavy chain constant region and a light chain comprising a human light chain variable region encoded by the rearranged human light chain variable region gene and a mouse light chain constant region encoded by the mouse light chain constant region gene;
• wherein the mouse does not produce fully human antibodies;
• (b) stimulating an immune response in the genetically modified mouse by exposing the genetically modified mouse to an antigen;
• and
• (c) obtaining the hybrid antibody from the serum of the genetically modified mouse.